In recent years, development is actively conducted for a liposome having a functional molecule introduced on the outer surface of the liposomal membrane to be used as a vector for delivering, to a target site, an intended substance such as low-molecular-weight medicines, nucleic acid medicines, antibody drugs, peptides, proteins, sugars, etc. In the field of biomedicine, research on nucleic acid medicines is actively conducted as a next-generation biomedicine that follows the footsteps of antibody drugs and protein medicines. Examples of nucleic acid medicines include antisenses, ribozymes, aptamers, decoy oligos, and siRNAs. Although clinical application of nucleic acid medicines is still in its early stage, siRNA has gathered attention in particular, and clinical tests thereof have been conducted by pharmaceutical companies and ventures in western countries. However, most of such clinical tests are limited to local administration. Although clinical tests are conducted for systemic administration using a delivery system, those have been limited to some organs expected to exhibit passive accumulation, such as the liver. Therefore, in order to expand the application range of a nucleic acid medicine represented by siRNA, there is a demand to establish a delivery system capable of active-targeting.
Examples of such a delivery system that has been developed include a liposome having a hydrophilic polymer (e.g., polyalkylene glycols such as polyethylene glycol) introduced on the outer surface of liposomal membrane (cf. Patent Literature 1 and Patent Literature 2). With this liposome, tropism of the liposome against tumor cells can be improved as a result of improvement in-blood retentivity of the liposome. Furthermore, multifunctional envelope-type nano device (MEND) (hereinafter, may be abbreviated as “MEND”) has been proposed, and this device can be used as a drug delivery system for selectively delivering a gene or a peptide into specific cells.
In addition, a liposome obtained by introducing GALA on the outer surface of the liposomal membrane using cholesterol bound with GALA has been developed (cf. Non-Patent Literature 1). When a liposome undergoes endocytosis, the liposome becomes included within an endosome, and the liposome within the endosome is degraded when the endosome fuses with a lysosome. However, with the above described liposome, a substance encapsulated in the liposome can escape from the endosome and can be released in the cytoplasm.
GALA is an oligopeptide formed from 30 amino acid residues of basically a repetitive sequence of glutamic acid, alanine, leucine, and alanine (EALA). GALA was synthesized by a research group of Szoka et al. (cf. Non-Patent Literature 2), and various studies have been conducted thereon hitherto. It is known that although GALA takes a random coil structure due to electric repulsion by glutamic acid under a neutral pH condition, GALA takes an alpha helix structure having high affinity with lipid membrane through resolving of the electrical repulsion under an acidic condition (cf. Non-Patent Literature 2).
Furthermore, GALA has been used as a pH responsive endosome-escape promotion element for improving MEND activity, since, when the surface of MEND is modified with a cholesterol (Chol)-bound GALA (Chol-GALA), an endosomal membrane and a MEND lipid membrane undergo membrane fusion under an acidic condition within the endosome, resulting in a release of an encapsulated substance into the cytoplasm (cf. Patent Literature 3).
As described above, although GALA has been used as a functional element for the purpose of improving intracellular kinetics, it is not known as a lung migratory element.
Furthermore, although lung is mentioned as a target organ of a certain type of liposome modified with an endosome soluble peptide (cf. Patent Literature 4), the configuration of the peptide described therein is largely different from the configuration of the GALA peptide according to the present application formed basically from a repetitive sequence of glutamic acid, alanine, leucine, and alanine (EALA). In addition, there is no disclosure or suggestion regarding a liposome modified with the peptide migrating specifically to the lung.